With the goal to understand and treat alcohol dependence better, since a few
years research in psychiatry focuses on the neurotransmitter glutamate.
Numerous animal experiments show that ethanol has an effect to different parts
of the glutamatergic system. It especially affects the function of the NMDA
receptor, whose metabolism adapts with chronical alcohol consumption. Due to
the loss of the ethanol induced inhibition, in alcohol withdrawal the brain
enters a state of hyperexcitability, which is accompanied with increased
concentration of glutamate and which is seen as the reason for an elevated
risk of seizures and withdrawal-correlated neurotoxicity. However, these
assumptions could not or only partly be confirmed by the few existing human
studies. Only the working group of Hermann (2011) showed an elevation of
glutamate in the anterior cingulate cortex (ACC) of alcohol dependent patients
in withdrawal. Thus, goal of this study was to confirm or to refute the
results of the numerous animal studies or gain new knowledge with a big number
of participants and, if possible, few external influencing factors. We
measured the absolute glutamate concentration in the ACC of 52 patients in
comparison with 75 healthy controls using 1H-MRS. At the time of the
measurement the patients have been abstinent for 12.2 days on average. This
work, which has been completed within the NGFN-plus study (Spanagel et al.,
2010), had two central assumptions: 1\. After the withdrawal of alcohol
alcohol dependent patients show a higher glutamate concentration in the ACC
than healthy controls. 2\. The glutamate concentration in the ACC depends on
the time of abstinence. To look for possible reasons for or consequences of
the increase in glutamate, we examined the relation between glutamate and some
clinical parameters, which have been of interest in animal studies before.
These were: number of abstinent days, number of previous withdrawals, severity
of withdrawal, life time alcohol consumption and pack years. The results
confirmed our first assumption and therefore the results of Hermann and
colleges: The glutamate in the ACC of the patient group was significantly
higher than of the control group. However, neither the number of abstinent
days, the number of previous withdrawals, the severity of withdrawal, nor the
life time alcohol consumption correlated with the glutamate level of the
patients. Furthermore, an effect of influencing factors as age, sex and
smoking habits could be excluded, which leaves the cause or possible clinical
consequences of the increase of the patients’ glutamate unexplained. Although
1H-MRS is the only non-invasive method, which allows detecting short-term
changes in the concentrations of metabolites in vivo, it has its limitations.
For example, it can’t distinguish between intra- and extra-cellular glutamate
concentrations and therefore can’t tell us about the acute to the
extracellular space released glutamate, which should affect the assumed
excitotoxicity in alcohol withdrawal. Moreover, postsynaptic processes, which
are mainly represented by the receptor function, can’t be detected by MRS.
Since it’s known that especially the NMDA receptors are influenced by
chronical alcohol consumption, it’s probable, that some effects of ethanol on
further components of the glutamatergic system and with that potential
consequences stayed undetected in our investigations. Despite of some
limitations due to methods, this work delivers fundamental statements about
the glutamatergic system of patients in alcohol withdrawal or early
abstinence, because it could detect increased glutamate concentrations in the
so far biggest population of patients. Thus, confirmed results of some animal
and human studies. Successful treatments with the glutamatergic active
withdrawal-medication Acamprosate suggest that, glutamatergic
neurotransmission plays a central role in the neurobiological changes in
alcohol dependence. Moreover, they emphasize the need for further research in
this area.